Lipid accumulation in tuberculosis granulomas inhibits macrophage-CD4⁺ T cell interactions and infection control

Granulomas form to contain Mycobacterium tuberculosis (Mtb) infection in the lung. What constitutes protective or detrimental responses is poorly understood. Here, using spatial transcriptomics and immunofluorescence microscopy of human lung samples and mouse models, we characterize the spatial structure and transcriptome of macrophage and T cell populations in tuberculosis granulomas. We identify signatures of reduced major histocompatibility complex (MHC) class II levels on macrophages and reduced CD4⁺ T cell activation, particularly in necrotic granulomas, suggesting a compromised interaction between innate and adaptive responses. Further analyses in mouse models and human cells reveal that infection of macrophages, or exposure to mycolic acids, disrupt cholesterol trafficking, leading to cholesterol accumulation and MHC class II sequestration in lysosomes. This inhibits antigen presentation and impairs anti-Mtb CD4⁺ T cell responses. Pharmacological restoration of cholesterol homeostasis during late-stage infection improves control of Mtb in mice. This study reveals an infection-driven mechanism of cholesterol overload, which impairs control of tuberculosis and could be targeted therapeutically.